EP3684780B1 - Synthèse de floxuridine - Google Patents

Synthèse de floxuridine Download PDF

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Publication number
EP3684780B1
EP3684780B1 EP18778972.2A EP18778972A EP3684780B1 EP 3684780 B1 EP3684780 B1 EP 3684780B1 EP 18778972 A EP18778972 A EP 18778972A EP 3684780 B1 EP3684780 B1 EP 3684780B1
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Prior art keywords
compound
formula
acid
group
fudr
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German (de)
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EP3684780A1 (fr
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Mani Bushan KOTALA
Venkata Lakshmi Narasimha Rao DAMMALAPATI
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Nucana PLC
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Nucana PLC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H1/00—Processes for the preparation of sugar derivatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/073—Pyrimidine radicals with 2-deoxyribosyl as the saccharide radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/06—Pyrimidine radicals
    • C07H19/10—Pyrimidine radicals with the saccharide radical esterified by phosphoric or polyphosphoric acids

Definitions

  • the present invention generally relates to a novel process for the preparation of floxuridine, an anti-cancer drug and a key intermediate in the synthesis of derivatives of floxuridine, such as NUC-3373 (5-fluoro-2'-deoxyuridine-5'-O-[1-naphthyl(benzoxy-L-alaninyl)] phosphate), a further anticancer drug.
  • NUC-3373 (5-fluoro-2'-deoxyuridine-5'-O-[1-naphthyl(benzoxy-L-alaninyl)] phosphate
  • Fluorouracil is a widely used anticancer drug, being used to treat colorectal cancer, esophageal cancer, stomach cancer, pancreatic cancer, breast cancer, cervical cancer, actinic keratosis and basal cell carcinoma.
  • Floxuridine is the corresponding deoxyuridine of 5-FU and is itself used to treat colorectal cancer and kidney cancer.
  • ProTides are masked phosphate derivatives of nucleosides. They have been shown to be particularly potent therapeutic agents in the fields of both antivirals and oncology. ProTides, more specifically, are prodrugs of monophosphorylated nucleosides. These compounds appear to avoid many of the inherent and acquired resistance mechanisms which limit the utility of the parent nucleosides (see, for example, ' Application of ProTide Technology to Gemcitabine: A Successful Approach to Overcome the Key Cancer Resistance Mechanisms Leads to a New Agent (NUC-1031) in Clinical Development', Slusarczyk et al., J. Med. Chem., 2014, 57, 1531-1542 ).
  • NUC-3373 (5-fluoro-2'-deoxyuridine-5'-O-[1-naphthyl(benzoxy-L-alaninyl)] phosphate) is a ProTide adaptation of FUDR.
  • NUC-3373 and a range of related compounds have shown activity in vitro against a range of cancer models, in many cases, and in particular for NUC-3373, that activity was outstanding and far superior to the results obtained with 5-FU or FUDR.
  • the addition of the ProTide phosphoramidate moiety to the FUDR molecule confers the specific advantages of delivering the key activated form of the agent (FUDR monophosphate) into the tumour cells.
  • NUC-3373 overcomes the key cancer cell resistance mechanisms associated with 5-FU and its oral pro-drug capecitabine, generating high intracellular levels of the active FdUMP metabolite, resulting in a much greater inhibition of tumour cell growth. Furthermore, in formal dog toxicology studies, NUC-3373 is significantly better tolerated than 5-FU (see WO2012/117246 ; McGuigan et al., 'Phosphoramidate ProTides of the anticancer agent FUDR successfully deliver the preformed bioactive monophosphate in cells and confer advantage over the parent nucleoside', J. Med.
  • FUDR is a key intermediate in many synthetic approaches to NUC-3373.
  • FUDR is typically produced by coupling the sugar portion with the nucleobase.
  • a key factor in the success of this coupling reaction is the diastereoselectivity that is achieved at the anomeric position.
  • the 5-FU portion is orientated in the ⁇ -position.
  • T. Lagerwall, et al., Tetrahedron Lett., 2015, 56, 5950-5953 discloses a series of ⁇ - and ⁇ -5-halo-2'-deoxyuridine derivatives prepared with anomeric selectivity using the conventional silylbase glycosylation method and taking advantage of the 3'-O-( N- acetyl)glycyl protection group and temperature control.
  • R. Noyori, et al., Chem. Lett., 1987, 16, 57-60 discloses condensation of 1-fluorofuranoses and silylated nucleobases catalysed by tetrafluorosilane.
  • the method may involve the formation of fewer impurities or lower amounts of particular impurities, particularly the undesired ⁇ -anomer of FUDR.
  • the method may provide an increased yield of FUDR.
  • a process for the preparation of FUDR in substantially diastereoisomerically pure form comprising step a) and optionally step b):
  • the step of reacting a compound of Formula Ia with a compound of Formula IIa may be carried out in a solvent S1 selected from acetonitrile (ACN), 1,2-dichloroethane (DCE) and dichloromethane (DCM).
  • a solvent S1 selected from acetonitrile (ACN), 1,2-dichloroethane (DCE) and dichloromethane (DCM).
  • the inventors have found that carrying out the coupling reaction in certain solvents provides improved reactions relative to those in the prior art including, for example, providing a better selectivity for the desired ⁇ -anomer.
  • the use of DCM was found to be particularly beneficial.
  • the inventors have found that carrying out the coupling reaction at lower temperatures provides a better selectivity for the desired ⁇ -anomer.
  • a process for preparing NUC-3373 in a second aspect of the invention, is provided a process for preparing NUC-3373.
  • a process of the first, second or third aspects of the invention further comprises converting the FUDR to NUC-3373:
  • R 1 and R 2 are the same. It is possible, however, that they may be different.
  • R 1 may be Si(C 1 -C 4 -alkyl) 3 .
  • the three C 1 -C 4 -alkyl groups may be the same.
  • R 1 may be Si(C 1 -C 3 -alkyl) 3 in which the C 1 -C 3 -alkyl groups are the same.
  • R 1 may be Si(C 1 -C 2 -alkyl) 3 in which the C 1 -C 2 -alkyl groups are the same.
  • Exemplary R 1 groups include t- butyldimethylsilyl, triisopropylsilyl, triethylsilyl and trimethylsilyl.
  • R 1 may be trimethylsilyl.
  • R 2 may be Si(C 1 -C 4 -alkyl) 3 .
  • the three C 1 -C 4 -alkyl groups may be the same.
  • R 2 may be Si(C 1 -C 3 -alkyl) 3 in which the C 1 -C 3 -alkyl groups are the same.
  • R 2 may be Si(C 1 -C 2 -alkyl) 3 in which the C 1 -C 2 -alkyl groups are the same.
  • Exemplary R 2 groups include t- butyldimethylsilyl, triisopropylsilyl, triethylsilyl and trimethylsilyl.
  • R 2 may be trimethylsilyl.
  • R 1 and R 2 are each trimethylsilyl (TMS).
  • TMS trimethylsilyl
  • the process may comprise the step of forming the compound of formula Ia .
  • the compound of forming the compound of formula Ia may comprise reacting 5-FU with an appropriate silylating agent SA1, optionally in the presence of a base B1, preferably a nitrogen base.
  • SA1 silylating agent
  • a base B1 preferably a nitrogen base.
  • R 3 and R 4 are the same and consist in a substituted or unsubstituted benzoyl protecting group.
  • R 3 and R 4 are each a 4-chlorobenzoyl group.
  • the compound of formula IIa may be a compound of formula IIb:
  • R 3 and/or R 4 are benzoyl (e.g. 4-chlorobenzoyl)
  • the step of removing R 3 and R 4 is carried out using methanolic ammonia solution.
  • X may be selected from halo, OC(O)-C 1 -C 4 -alkyl, O-C 1 -C 4 -alkyl, and OH.
  • X may be selected from halo and OC(O)-C 1 -C 4 -alkyl. It may be that X is halo. It may be that X is Cl.
  • the compound of formula IIa may be a compound of formula IIc:
  • A1 may be selected from a Lewis acid, a sulfonic acid, a phenol and a carboxylic acid.
  • A1 may be selected from a Lewis acid, a sulfonic acid, and a carboxylic acid.
  • A1 may be a sulfonic acid.
  • A1 may be selected from camphor sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid. The acid may be p-toluenesulfonic acid.
  • T1 may be below room temperature.
  • T1 may be below 25 °C.
  • T1 may be below 20 °C.
  • T1 may be in the range from 5 °C to 18 °C.
  • T1 may be in the range from 9 °C to 15 °C.
  • the process of the first, second or third aspects of the invention may further comprise converting the FUDR to NUC-3373, thus providing a process of providing NUC-3373:
  • step d) may comprise step d) and optionally steps c) and e):
  • R 6 may be H.
  • R 6 may be independently selected from silyl protecting group, ester protecting group, carbonate protecting group, benzyl protecting group optionally substituted -C(aryl) 3 , and -C 1 -C 2 -alkyl-O-C 1 -C 4 -alkyl.
  • R 6 may be independently selected from optionally substituted -Si(C 1 -C 6 -alkyl) 3 , optionally substituted -C(O)-OC 1 -C 6 -alkyl and optionally substituted -C(O)OCH 2 -aryl, - C(O)-O-allyl.
  • R 6 is selected from -C(O)OtBu, and -C(O)O-benzyl.
  • R 6 may be -C(O)OCH 2 -aryl.
  • R 6 may be -C(O)OtBu.
  • R 6 may be independently selected from optionally substituted -C(O)-C 1 -C 6 -alkyl and optionally substituted -C(O)-aryl, e.g. R 6 may be independently selected from benzoyl and acetyl.
  • R 6 may be optionally substituted -Si(C 1 -C 6 -alkyl) 3 .
  • R 6 may be - Si(C 1 -C 4 -alkyl) 3 .
  • the alkyl groups may be unsubstituted.
  • R 6 may be t-butyldimethylsilyl.
  • R 5 may be halo.
  • R 5 may be a sulfonate.
  • R 5 may be a phenolic leaving group in which the phenol is substituted with from 1 to 5 electron withdrawing groups.
  • NUC-3373 can exist in two diastereomeric forms, differing in the configuration about the phosphorous chiral centre.
  • the diastereoisomer having the (S)-configuration at the phosphorous is known herein as the (Sp)-Nuc-3373 diastereoisomer and the diastereoisomer having the ( R )-configuration at the phosphorous chiral centre is known herein as the corresponding ( R p)-diastereoisomer
  • the process comprises a method of making NUC-3373 in diastereomerically enriched form with respect to the phosphorous chiral centre.
  • the compound of formula IVa is a compound of Formula IVb: wherein R 7 represents an electron withdrawing group and a is an integer from 1 to 5; and wherein the compound of formula IVb is in substantially diastereomerically pure form.
  • Illustrative electron withdrawing groups include: halo group (e.g. selected from fluoro, bromo, chloro or iodo); trifluoromethyl, cyano and nitro.
  • a is an integer between 1 and 5.
  • R 7 may be at each occurrence halo, e.g. fluoro.
  • For (R 7 ) a a may be 5.
  • compounds of Formula IVb can exist in two diastereomeric forms differing in the configuration about the phosphorous chiral centre (IVc and IVd diastereoisomers).
  • the identity and position of the R 7 groups on the phenoxy leaving group may affect the priority (according to the Cahn-Ingold-Prelog rules) of the various groups attached to the phosphorous so the generic formulae IVc and IVd cannot be assigned as Rp or Sp.
  • IVc diastereomer provides the (Sp)-diastereoisomer of NUC-3373 and IVd provides the (Rp)-diastereoisomer of NUC-3373.
  • the process comprises converting FUDR into the (Sp)-diastereoisomer of NUC-3373 in diastereomerically enriched form, and the compound of formula IVb is the IVc diastereoisomer in diastereomerically enriched form.
  • the process comprises converting FUDR into the (Rp)-diastereoisomer of NUC-3373 in diastereomerically enriched form, and the compound of formula IVb is the IVd diastereomer in diastereomerically enriched form.
  • the base (B2) might be a nitrogen base.
  • the base (B2) may be an organometallic base or metal hydride base (e.g. NaH).
  • the base may be a Grignard reagent (i.e. an alkylmagnesium halide).
  • Step d) may be carried out in a solvent S2.
  • the organic solvent S2 is preferably an ether.
  • the solvent S2 is tetrahydrofuran.
  • the process may comprise the diastereoisomeric enrichment of a compound of Formula IVb; the process comprising:
  • the IVc diastereoisomer of a compound of formula IVb can then be used in step d) of the process described above to provide (Sp)-NUC-3373.
  • the inventors have surprisingly found that upon treating compounds of formula IVb with a base, they isomerise, preferentially forming the IVc diastereoisomer over the IVd diastereoisomer.
  • the IVd diastereoisomer can be converted to the IVc diastereoisomer or an epimeric mixture of the IVd diastereoisomer and the IVc diastereoisomer can be converted to the !Vc diastereoisomer.
  • This increases the net efficiency of any synthetic sequence for making the (Sp)-diastereoisomer of NUC-3373.
  • the base (B3) may be selected from the group consisting of organic amine bases (e.g. primary, secondary, tertiary amines, cyclic amine; exemplary organic amine bases include bases include N-alkylimidazoles, (e.g. N-methyl imidazole (NMI)), imidazole, optionally substituted pyridines, (e.g. collidine, pyridine, 2,6-lutidine) and trialkylamines (e.g. triethylamine, and diisopropylethylamine)); or inorganic bases (e.g. alkali metal hydroxide, alkali metal carbonates, alkali metal alkoxides, alkali metal aryloxides).
  • B3 is a tertiary amine.
  • B3 may be a trialkylamine.
  • B3 is triethylamine.
  • the solvent S3 may be selected from the group consisting of amides, ethers, esters, ketones, aromatic hydrocarbons, halogenated solvents, nitriles, sulfoxides, sulfones and mixtures thereof.
  • S3 may be an organic solvent.
  • Organic solvents include but are not limited to ethers (e.g. tetrahydrofuran, 1,4-dioxane, diethyl ether, t- butylmethylether); ketones (e.g. acetone and methyl isobutyl ketone); halogenated solvents (e.g. dichloromethane, chloroform and 1,2-dichloroethane); hydrocarbons (e.g.
  • S3 is a hydrocarbon or is a mixture comprising a hydrocarbon. Where S3 is a mixture, it may be a mixture that comprises over 50% (e.g. over 70%) of the hydrocarbon S3 may be a hydrocarbon.
  • the hydrocarbon may be hexane.
  • the hydrocarbon may be heptane.
  • S3 may be a mixture of hexane or heptane and a relatively more polar organic solvent (e.g. an ether, ester, alcohol or halogenated solvent).
  • S3 may be a mixture of hexane or heptane and a polar organic solvent, the mixture comprising over 50% (e.g. over 70%) by volume hexane or heptane.
  • S3 may be a mixture of hexane or heptane and ethyl acetate.
  • S3 may be a mixture of heptane and ethyl acetate.
  • S3 may be a mixture of hexane or heptane and ethyl acetate, the mixture that comprising over 50% (e.g. over 70%) by volume hexane or heptane.
  • S3 may be a mixture of heptane and ethyl acetate, the mixture comprising over 50% (e.g. over 70%) by volume heptane.
  • S3 may be a mixture of hexane or heptane and methyl-tert-butyl ether.
  • S3 may be a mixture of hexane and methyl-tert-butyl ether.
  • S3 may be a mixture of hexane or heptane and methyl-tert-butyl ether, the mixture that comprising over 50% (e.g. over 70%) by volume hexane or heptane.
  • S3 may be a mixture of hexane and methyl-tert-butyl ether, the mixture comprising over 50% (e.g. over 70%) by volume hexane.
  • Step y) may involve stirring the mixture of the compound of formula IVb and the base B3 for 24 h or longer.
  • Step y) may involve stirring the mixture of the compound of formula IVb and the base B3 for 48 h or longer.
  • Step y) may involve stirring the mixture of the compound of formula IVb and the base B3 for 60 h or longer.
  • Step y) may involve stirring the mixture of the compound of formula IVb and the base B3 for 72 h or longer.
  • Step y) may involve stirring the mixture of the compound of formula IVb and the base B3 for up to 100 h.
  • the compound of Formula IVb is a compound selected from:
  • the compound of formula IVb may be compound IVe:
  • the compound of formula IVb may be compound IVf:
  • the invention may also provide a pharmaceutical composition comprising a compound of the fifth and sixth aspects of the invention and a pharmaceutically acceptable excipient.
  • the invention may also provide a method of treating cancer (e.g. a solid tumour or leukaemia), the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the fifth and sixth aspects of the invention.
  • cancer e.g. a solid tumour or leukaemia
  • the compounds of the fifth and sixth aspects of the invention may be for medical use.
  • the compounds of the fifth and sixth aspects of the invention may be for use in treating cancer (e.g. a solid tumour or leukaemia).
  • a protecting group for a hydroxyl group may be independently selected from silyl protecting group, ester protecting group, carbonate protecting group, benzyl protecting group optionally substituted -C(aryl) 3 , and -C 1 -C 2 -alkyl-O-C 1 -C 4 -alkyl.
  • a silyl protecting group is typically an optionally substituted -Si(C 1 -C 6 -alkyl) 3 group.
  • a silyl protecting group can also be a t-butyldimethylsilyl group.
  • the group optionally substituted -Si(C 1 -C 6 -alkyl) 3 may be a -Si(C 1 -C 4 -alkyl) 3 group.
  • the group is (i.e. the alkyl groups are) preferably unsubstituted.
  • Illustrative examples include triethylsilyl, triisopropylsilyl and t-butyldimethylsilyl.
  • An ester protecting group may be selected from optionally substituted -C(O)-C 1 -C 6 -alkyl and optionally substituted -C(O)-aryl.
  • the group optionally substituted -C(O)-C 1 -C 6 -alkyl may be a -C(O)-C 1 -C 6 -alkyl group.
  • the group i.e. the alkyl group
  • Illustrative examples include acetyl and propionyl.
  • the group optionally substituted -C(O)-aryl may be a -C(O)-phenyl group.
  • -C(O)-phenyl groups may also be known as benzoyl protecting groups.
  • the group i.e. the phenyl group
  • Illustrative examples include benzoyl and 4-chlorobenzoyl.
  • a carbonate protecting group may be selected from optionally substituted -C(O)-C 1 -C 6 -alkyl, optionally substituted -C(O)OCH 2 -aryl, -C(O)-O-allyl and -C(O)-O-CH 2 -fluorenyl.
  • the group optionally substituted -C(O)-OC 1 -C 6 -alkyl may be a -C(O)-OC 1 -C 4 -alkyl group.
  • the group (i.e. the alkyl group) is preferably unsubstituted.
  • Illustrative examples include -C(O)-O-methyl and -C(O)-O-ethyl.
  • a particularly preferred example is C(O)O t Bu.
  • the group optionally substituted -C(O)OCH 2 -aryl is preferably an optionally substituted -C(O)Obenzyl group.
  • Illustrative examples include -C(O)Obenzyl and - C(O)O-(4-methoxybenzyl).
  • a benzyl protecting group is an optionally substituted -(C 1 -alkylene)-aryl group.
  • the group optionally substituted -(C 1 -alkylene)-aryl.
  • Illustrative examples include benzyl, 1-ethylbenzene (-CH(Me)Ph), 4-methoxy benzyl, 4-nitrobenzyl, 4-bromobenzyl, 2,3-dimethoxybenzyl and 2,4-dimethoxybenzyl.
  • the group optionally substituted -C 1 -C 2 -alkyl-O-C 1 -C 4 -alkyl may be a -C 1 -C 2 -alkyl-O-C 1 -C 2 -alkyl group.
  • the group is (i.e. the alkyl groups are) preferably unsubstituted.
  • Illustrative examples include methoxymethyl (MOM) and 2-methoxyethoxymethyl (MEM).
  • the group optionally substituted -C(aryl) 3 may be a -C(phenyl) 3 group.
  • Illustrative examples include trityl.
  • Exemplary Grignard reagents include t-butylmagnesium halides such as t -BuMgCI, t- BuMgBr.
  • the base B1 is t-BuMgCl.
  • Exemplary nitrogen bases include N -alkylimidazoles, (e.g. N -methyl imidazole (NMI)), imidazole, optionally substituted pyridines, (e.g. collidine, pyridine, 2,6-lutidine) and trialkylamines (e.g. triethylamine, and diisopropylethylamine).
  • N -alkylimidazoles e.g. N -methyl imidazole (NMI)
  • imidazole optionally substituted pyridines, (e.g. collidine, pyridine, 2,6-lutidine) and trialkylamines (e.g. triethylamine, and diisopropylethylamine).
  • silylating agents include silyl chlorides, silylsulfonates (e.g. triflates) and hexamethyldisilazane.
  • Exemplary Lewis acids include SnCl 4 , TiCl 4 , Ti(OR) 4 AlMe 3 , AlMe 2 Cl, AlMeCl 2 , AlCl 3 , BF 3 sources (eg. BF 3 ⁇ OEt 2 and BF 3 ⁇ SMe 2 ), BCl 3 , B(C 6 F 5 ) 3 , FeCl 3 , Yb(OTf) 3 , InBr 3 , and thioureas.
  • Exemplary phenols that can be used as acids in the methods of certain aspects of the invention include those having electron withdrawing groups attached to the benzene ring. Examples include pentafluorophenol, 2-nitrophenol, 3-nitrophenol and 4-nitrophenol.
  • carboxylic acids include alkyl carboxylic acids, e.g. acetic acid, propionic acid and aryl carboxylic acids, e.g. benzoic acid.
  • Exemplary sulfonic acids include camphor sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid.
  • 'diastereomerically enriched form' and 'substantially diastereomerically pure form' means a diastereoisomeric purity of greater than 95%.
  • 'Diastereomerically enriched form' and 'substantially diastereomerically pure form' may mean a diastereoisomeric purity of greater than 98%, greater than 99% or greater than 99.5%.
  • any of the aforementioned aryl groups are optionally substituted, where chemically possible, by 1 to 3 substituents which are each independently at each occurrence selected from the group consisting of: halo, nitro, cyano, NR a R a , NR a S(O) 2 R a , NR a CONR a R a , NR a CO 2 R a , OR a ; SR a , SOR a , SO 3 R a , SO 2 R a , SO 2 NR a R a , CO 2 R a C(O)R a , CONR a R a , C 1 -C 4 -alkyl, C 2 -C 4 -alkenyl, C 2 -C 4 -alkenyl, and C 1 -C 4 haloalkyl; wherein R a is independently at
  • any of the aforementioned aryl (e.g. phenyl, including the phenyl groups in benzyl groups) groups are optionally substituted by 1 to 3 substituents which are each independently at each occurrence selected from the group consisting of: halo, nitro, OR a ; C 1 -C 4 -alkyl, C 1 -C 4 haloalkyl; wherein R a is independently at each occurrence selected from H, C 1 -C 4 alkyl and C 1 -C 4 haloalkyl.
  • Aryl groups have from 6 to 20 carbon atoms as appropriate to satisfy valency requirements.
  • Aryl groups are carbocyclic groups which satisfy the Huckel rule (i.e. they contain a carbocyclic ring system containing 2(2n + 1) ⁇ electrons).
  • Aryl groups may be optionally substituted phenyl groups, optionally substituted biphenyl groups, optionally substituted naphthalenyl groups or optionally substituted anthracenyl groups.
  • aryl groups may include non-aromatic carbocyclic portions.
  • an aryl group is an optionally substituted phenyl group.
  • Alkyl groups may be straight chain or branched.
  • a C 4 alkyl group could be n-butyl, i-butyl or t-butyl.
  • Alkylene groups are alkyl bi-radicals. Examples include -CH 2 - and -CH 2 CH 2 -. A C1-alkylene group may be -CH 2 - or -CHMe-.
  • Organic solvents include but are not limited to acetonitrile, ethers (e.g. tetrahydrofuran, 1,4-dioxane, diethyl ether, methyl- tert -butyl ether); ketones (e.g. acetone and methyl isobutyl ketone); halogenated solvents (e.g. dichloromethane, chloroform and 1,2-dichloroethane); and amides (e.g. DMF, NMP); or mixtures thereof.
  • ethers e.g. tetrahydrofuran, 1,4-dioxane, diethyl ether, methyl- tert -butyl ether
  • ketones e.g. acetone and methyl isobutyl ketone
  • halogenated solvents e.g. dichloromethane, chloroform and 1,2-dichloroethane
  • amides e.g. DMF,
  • the organic solvent is most preferably a halogenated solvent or an amide.
  • Step d) is typically conducted at a suitable temperature, e.g. from about -5°C to about 40°C.
  • the reaction temperature is about 25°C to about 30°C.
  • the reaction may be allowed to stir for a period of time from about 15 mins to about 16 h and preferably from about 30 mins to about 60 mins.
  • the processes of the invention may also involve deprotection of the hydroxy protecting groups.
  • step b is carried out without purifying the product of step a. It may be that the deprotection step (step e) is carried out without purifying the product of step d).
  • a protecting group is acid labile (e.g. trityl, C(O)O t Bu, MOM, MEM, 2,4-dimethoxybenzyl, 2,3-dimethoxybenzyl, -C(Me) 2 -)
  • the deprotection step can be conducted using a suitable acid.
  • the acid may be a Bronsted acid (e.g. TFA, phosphoric acid, HCl, or formic acid) or a Lewis acid (e.g. ZnBr 2 , CeCl 3 ).
  • Lewis acids e.g. ZnBr 2
  • HCl is likewise less preferred.
  • the acid is TFA.
  • a protecting group is base sensitive, e.g. acetyl, benzoyl, 4-chlorobenzoyl
  • the deprotection step can be conducted using a suitable base, e.g. aqueous NH 3 , methanolic ammonia solution, aqueous NaOH.
  • Base sensitive groups may be less preferred for R 6 .
  • a protecting group is a silyl group (e.g. triethylsilyl or t -butyldimethylsilyl
  • the deprotection step can be conducted using a suitable acid (e,g, TFA) or using a suitable fluoride source (e.g. tetrabutylammonium fluoride, fluorosilicic acid, HF).
  • a suitable acid e.g, TFA
  • a suitable fluoride source e.g. tetrabutylammonium fluoride, fluorosilicic acid, HF.
  • a protecting group is a benzyl group or a C(O)Obenzyl group
  • the deprotection step can be conducted using H 2 and a suitable catalyst (e.g. Pd/C).
  • a suitable catalyst e.g. Pd/C
  • Such protecting groups may be less preferred.
  • a protecting group is a 4-methoxybenzyl, 2,3-dimethoxybenzyl, 2,4-dimethoxybenzyl or C(O)O-(4-methoxybenzyl)
  • the deprotection step can be performed using a suitable oxidizing agent (e.g. meta -chloroperbenzoic acid).
  • the deprotection step can be performed using (PPh 3 ) 4 Pd and an appropriate nucleophilic scavenger for the allylic cation such as NaBH 4 or N , N -dimethylbarbituric acid.
  • the deprotection step can be performed using piperidine.
  • the deprotection step may be conducted in an organic solvent or a mixture thereof.
  • organic solvents include, but are not limited to halogenated solvents (e.g. dichloromethane, chloroform, 1,2-dichloroethane); alcohols (e.g. methanol, ethanol, isopropanol) and ethers (e.g. tetrahydrofuran, diethyl ether).
  • the organic solvent is preferably a halogenated solvent, e.g. dichloromethane.
  • the deprotection reaction may be carried out at a temperature in the range of, for example -10°C to about 30°C, e.g. to about 10°C.
  • a convenient temperature to carry out the reaction is -5°C to 5°C.
  • the reaction may be allowed to stir for a period of time from about 15 mins to about 16 hours and preferably from about 1 hour to about 4 hours, and more preferably from about 2 hours to about 3 hours.
  • the deprotection is performed in the presence of an acid (e.g. TFA)
  • isolation of the product obtained after the deprotection is typically done by quenching the excess acid used in deprotection step with an appropriate base, and extracting the product with a water immiscible organic solvent and recovering the product by evaporation of the organic solvent.
  • an acid e.g. TFA
  • water immiscible organic solvents useful in extraction include esters such as ethyl acetate, methyl acetate, isopropyl acetate and the like; chlorinated solvents such as dichloromethane, chloroform and the like; aromatic hydrocarbon solvents such as toluene, xylene and the like; preferably ethyl acetate.
  • Example 1 Preparation of 3',5'-di-O-(4-chlorobenzoyl)-5-fluoro-2'- ⁇ -deoxyuridine 3 (an illustrative example of a compound of formula Illa).
  • reaction mass was cooled to 25 °C, CH 2 Cl 2 (225 ml., 4 v/w of the preceding mass) was added, and then the reaction was cooled to 5 °C.
  • 1-Chloro-3,5-di-(4-chlorobenzoyl)-2-deoxy-d-ribose 2 50 g, 0.0582 mol is 25g 0.1168 mol is 50 g
  • CH 2 Cl 2 25 mL, 0.5 v/w
  • p-Toluene sulfonic acid monohydrate (2.214 g, 0.01164 moles) was added at 5 °C, the temperature was raised to 12 ⁇ 3 °C and subsequently stirred for 20-24 h (if the temperature increases above 15 °C the proportion of the ⁇ -anomer increases.).
  • reaction was transferred into a 2 L flask containing isopropanol (i PrOH) (250 mL, 5 v/w) at 25 °C, using an additional i PrOH (500 mL) to aid transfer.
  • i PrOH isopropanol
  • the reaction slurry was stirred for 2-3 h at 25 °C after which it was filtered under vacuum and washed with i PrOH (100 mL at 25 °C).
  • the moist filter cake was recrystallized from acetic acid (750 mL, 15 v/w) at 80 °C by cooling to 25 °C gradually over 2 h.
  • the Celite ® was washed with MeOH (100 mL, 2 v/w) and the combined filtrate was concentrated to between 50-100 mL under vacuum (600 mmHg, ⁇ 45 °C). Ethyl acetate was added (100 mL, 2 v/w), then concentrated under vacuum to approximately 50-100 mL. More ethyl acetate (350 mL, 7 v/w) was added and the resulting slurry was maintained at 30 °C for 2-3 h. The reaction slurry was then filtered under vacuum and washed with ethyl acetate (100 mL, 2 v/w).
  • Alpha-naphthol 4 (100 g) was dissolved in DCM (1 L) at 25°C and POCl 3 (1.1 eq) was added at 25°C and stirred for 10 min before the mixture was cooled to -70°C and stirred for 10 min.
  • POCl 3 1.1 eq
  • Triethylamine (1.1 eq.) was added slowly maintaining the temperature at below -70°C and the mixture was stirred for 1 h at -70°C. The mixture was warmed to 25°C and stirred for 1h before being cooled to -50°C.
  • L-alanine benzyl ester 6 (HCl salt; 1 eq.) was added to the mixture which stirred for 10 min before triethylamine (2.2 eq) in DCM (200 mL) was added at -50°C over 30 minutes. The mixture was stirred for 1 h at -50°C before being warmed to 25°C and stirred for a further 1h. The mixture was cooled to -10°C and stirred for 10 min before pentafluorophenol 8 in DCM (200 mL) was added to the reaction mass slowly at below -10°C. The mixture was stirred at -10°C for 10 min before triethylamine (1.1 eq.) was added over 30 min at -10°C.
  • 50% IPA/water (2.4 L) was added to the crude compound and stirred for 1 h at 25°C. The solid compound was filtered and the wet cake was washed with 50% IPA /water (500 mL) before being dried in vacuo. Again 50% IPA /water (2.4 L) was added to the crude compound and stirred for 1 h at 25°C before being filtered and the wet cake was again washed with 50% IPA /water (500 mL) before being dried in vacuo.
  • the semi-dried compound was washed with cyclohexane (10 v/w) at 25-30°C for 1 h before the solid compound was washed with cyclohexane (2 L) and the wet compound 9 was dried under vacuum at 55-60°C °C for 12 h
  • the diastereoisomers of compound 9 were separated by HPLC with Biotage Isolera using C18 SNAP Ultra (30 g) cartridge with a mixture of MeOH/H 2 O (70%/30%) as an eluent to give: the fast eluting isomer (believed to be the Rp diastereoisomer) and the slow eluting isomer (believed to be the Sp diastereoisomer)
  • Isomers are named as fast eluting (FE) and slow eluting (SE) based on retention time on C18 (reversed phase) cartridge and HPLC analytical column.
  • the stereochemistry ( R p vs S p) of the two compound 9 isomers described above has been tentatively assigned on the basis of comparison of 31 P chemical shift, 1 H NMR spectra, and HPLC retention times of the NUC-3373 isomers made using the compound 9 isomers with those of other ProTides known in the literature.
  • the stereochemistry of the phosphate stereocentre is inverted during the process of the invention so the ( S )-diastereoisomer of compound 9 will form the ( S )-diastereoisomer of NUC-3373 and likewise the ( R )-diastereoisomer of compound 9 will form the (R)-diastereoisomer of NUC-3373.
  • the stereochemical assignment is supported by powder X-ray diffraction and differential scanning calorimetry that has been carried out on the two compound 9 isomers, but this is not in itself definitive.
  • 3'-BOC protected FUDR 12 (an illustrative example of a compound of formula Va ) can be made according to the following scheme.
  • Compound 12 can then be coupled with a compound of formula IVb.
  • the Rp isomer of NUC-3373 can be accessed by performing the above process but starting with the Rp diastereoisomer of compound 9 :

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Claims (12)

  1. Procédé de préparation de FUDR à une pureté diastéréoisomérique supérieure à 95 % :
    Figure imgb0037
     le procédé comprenant l'étape a) et éventuellement l'étape b) :
    a) réaction d'un composé de Formule Ia avec un composé de Formule IIa en présence d'un acide A1 pour obtenir un composé de Formule IIIa ayant une pureté diastéréoisomérique supérieure à 95 % :
    Figure imgb0038
    Figure imgb0039
     R1 et R2 étant chacun indépendamment des groupes trialkylsilyle ; R3 et R4 étant chacun un groupe benzoyle substitué ou non substitué ; et X étant un groupe partant ; et
    b) élimination du groupe protecteur R3 et R4 du composé de Formule IIIa pour obtenir une FUDR ayant une pureté diastéréoisomérique supérieure à 95 % ;
    l'étape de réaction d'un composé de Formula Ia avec un composé de Formule Ila étant réalisée à une température T1 comprise entre 9 °C et 15 °C.
  2. Procédé selon la revendication 1, dans lequel l'étape de réaction d'un composé de Formule Ia avec un composé de Formule IIa est effectuée dans un solvant S1 choisi parmi l'acétonitrile (ACN), le 1,2-dichloroéthane (DCE) et le dichlorométhane (DCM).
  3. Procédé selon la revendication 1 ou la revendication 2, dans lequel l'acide A1 est choisi parmi un acide de Lewis, un acide sulfonique et un acide carboxylique.
  4. Procédé selon la revendication 3 dans lequel l'acide est un acide sulfonique.
  5. Procédé selon la revendication 4 dans lequel l'acide est un acide p-toluènesulfonique.
  6. Procédé selon l'une quelconque des revendications précédentes, dans lequel l'étape de réaction d'un composé de Formule Ia avec un composé de Formule IIa est effectuée dans un solvant S1 qui est le dichlorométhane (DCM).
  7. Procédé selon l'une quelconque des revendications précédentes, dans lequel R1 et R2 sont chacun triméthylsilyle.
  8. Procédé selon l'une quelconque des revendications précédentes, dans lequel R3 et R4 sont chacun un groupe 4-chlorobenzoyle.
  9. Procédé selon la revendication 8, dans lequel R3 et R4 sont éliminés à l'aide d'une solution d'ammoniac méthanolique.
  10. Procédé selon l'une quelconque des revendications précédentes, dans lequel X et Cl.
  11. Procédé selon l'une quelconque des revendications précédentes, ledit procédé comprenant en outre la conversion de la FUDR en NUC-3373 :
    Figure imgb0040
  12. Procédé selon la revendication 11, dans lequel la FUDR est convertie en NUC-3373 dans un procédé comprenant l'étape d) et éventuellement comprenant les étapes c) et e) :
    c) éventuellement conversion de la FUDR en un composé de Formule Va dans lequel R6 est un groupe protecteur ;
    d) réaction d'un composé de Formule Iva ; avec un composé de Formule Va en présence d'une base (B2) pour obtenir un composé de Formule Via ; R5 étant un groupe partant et R6 étant indépendamment choisi parmi H (auquel cas le composé de Formule Va est FUDR) et un groupe protecteur :
    Figure imgb0041
    Figure imgb0042
    e) R6 étant un groupe protecteur, éventuellement élimination du groupe protecteur R6 du composé de Formule VIa pour obtenir NUC-3373.
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